Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-20
1999-08-31
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
530300, 548538, 549172, 560 27, 564138, 564139, 564140, 564141, C07C23102, C07K 108, C07K 106
Patent
active
059455438
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a novel process for the racemization-free linkage of .alpha.-(N,N-dialkyl)-amino acids with amines to give the corresponding carboxamides.
There is interest in .alpha.-(N,N-dialkyl)-amino acids of the formula II ##STR2## as building blocks for the synthesis of numerous natural substances with an interesting profile of pharmacological actions and for active substances structurally derived from these substances (enkephalins: U. Schmidt et al.; Liebigs Ann. Chem. (1985) 1254-1262, dolastatins: G. R. Pettit et al.; Tetrahedron 49 (41) 9151-9170, WO 93/23 424). Thus, for example, the antineoplastic active substance dolastatin 10 is prepared from N,N-dimethylvaline (IIa) and a tetrapeptide: ##STR3## The linkage of an N,N-dialkylamino acid such as IIa with peptides is difficult and, in the case of dolastatin 10, gave a yield of only 53% (J. Poncet et al. Tetrahedron 50, (1994) 5345-5360). This poor result, which leads to loss of a large portion of the valuable tetrapeptide in the dolastatin synthesis, is not surprising according to U. Schmidt et al. (Liebigs Ann. (1985) 1254-1262).
U. Schmidt also investigated the linkage of N,N-dimethylamino acids in connection with the synthesis of enkephalins. In this connection, only three methods proved to be useful for activating these amino acids: pentafluorophenyl esters: ##STR4## This method is used, for example, by G. R. Pettit et al. (J. Am. Chem. Soc. 113 (1991) 6992-6993) for synthesizing dolastatin 15. The starting compound required for this multistage process is pentafluorophenol, a costly reagent which is not available in sufficient quantity for industrial syntheses. Its use moreover leads to fluorine-containing waste which can be disposed of only with difficulty and possibly with formation of dioxins. 3-cyano-4,6-dimethyl-2-pyridinethiol: ##STR5## However, the cyanopyridine is not commercially available and must be prepared in a multistage process. phosphocyanidate (=DEPC) (G.R. Pettit, Tetrahedron 50 (1994), 42, 12097-12108). This reagent is also not commercially available in the amounts necessary for industrial synthesis. An additional multistage process is necessary. Highly toxic cyanide-containing solutions must be used in the preparation and reaction of DEPC.
There is thus a pressing need for processes which make simple linkage of N,N-dimethylamino acids possible.
However, there is interest not only in peptide linkage of N,N-di-methylamino acids but also in peptide couplings with N-benzyl-N-methylamino acids. In this case, the benzyl radical acts as protective group which can easily be eliminated by hydrogenolysis.
Although N-benzyl-N-methylamino acids can easily be prepared as peptide building blocks, they are little used because to date there have been no methods which can be used for racemization-free linkage of these amino acids.
This is why peptides which are partly composed of N-methylamino acids (eg. cyclosporins, dolastatins) are prepared exclusively using N-acyl-N-methylamino acids (acyl=butoxycarbonyl (BOC), benzyloxycarbonyl (Z)) which, although more difficult to prepare than N-benzyl-N-methylamino acids, are less prone to racemization on linkage (example: Dolestatin 15 synthesis by G. R. Pettit, J. Am. Chem. Soc. 113 (1991) 6692-6693).
A suitable coupling reagent for using N-benzyl-N-methylamino acids would therefore also be desirable.
Linkage of carboxylic acids with amines in the presence of anhydrides of alkanephosphonic acids to give the corresponding amides is a familiar process (EP 14 834) which can also be used to prepare peptides (EP 156 280). n-Propanephosphonic anhydride (PPA) is preferably used for this purpose. However, the utilizability of this reagent has been shown only for N-acylamino acids which are not alkylated on the nitrogen.
Numerous coupling reagents are available for such reactions. The utilizability of anhydrides of alkanephosphonic acids for linking N,N-dialkylamino acids of the formula I has not hitherto been investigated.
It was therefore surprising in the context of the problems indicated abov
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Tetrahedron, vol. 50, No. 18, 5345-5360 1994 Roux et al.
J. Am. Chem. Soc. 1991, 113, 6692-6693 Petit et al.
Liebig, Ann. Chem. Schmidt et al. 1254-1257 (1985).
Tetrahedron, vol. 49, No. 41, Oct. 1993 Petit et al II.
Buschmann Ernst
Zierke Thomas
BASF - Aktiengesellschaft
Higel Floyd D.
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